tbuckley/cabot-search huggingface dataset:
Abstract 526: Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring
Authors: Patrick Peiyong Ye, Robb Viens, Xavier Bower, Shan Riku, David Tsao, Oguzhan Atay
Journal: Cancer Research (2022)

Abstract As novel cancer treatments become available, the need to quickly and accurately evaluate whether these treatments are effective remains unaddressed. Obtaining earlier feedback on the efficacy of a cancer therapy could prevent a poor treatment outcome by switching to a more effective therapy sooner. Levels of circulating tumor DNA (ctDNA) have been found to be prognostic of tumor progression, suggesting that a non-invasive liquid biopsy assay could provide longitudinal ctDNA measurements that accurately track tumor progression. However, while there is interest in using existing minimal residual disease (MRD) detection and treatment selection liquid biopsy assays for treatment monitoring applications, they both suffer from limitations in their ability to precisely and sensitively quantify trends in tumor progression over the course of treatment. In addition, tumor-informed MRD detection assays are often infeasible for treatment monitoring due to unavailability of the initial tissue sample. We have developed and validated a novel methylation-based liquid biopsy assay for pan-cancer treatment monitoring without the need to obtain a sample from the tumor itself. Methylation has long been shown to be a strong and consistent biomarker for cancer, and because tumor tissue has widespread differential methylation across the genome compared to normal tissue, we are able to overcome molecule sampling limitations. In analytical validation, our assay could detect as small changes as 0.05%, e.g., an elevation of tumor fraction from 0.5% to 0.55%, a level of precision that is an order-of-magnitude better than any available assays. Next, we tested our assay on clinical specimens by measuring ctDNA in serially collected blood samples from subjects with cancer. As would be expected from the high level of precision, we were able to successfully demonstrate the predictive power of ctDNA measurements for clinical outcomes. These results from our methylation-based liquid biopsy assay open the path to earlier and extremely precise treatment monitoring for oncologists and their patients. Citation Format: Patrick Peiyong Ye, Robb Viens, Xavier Bower, Shan Riku, David Tsao, Oguzhan Atay. Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 526.
Abstract 5287: Aggregation of HER2 receptors on the tumor cell surface induced by a novel anti-HER2 bispecific antibody led to enhanced tumor cell growth inhibition
Authors: Lan Deng, Jie Zhao, Xiaoqing Meng, Aotian Xiao, Zhenping Zhu, Haomin Huang
Journal: Cancer Research (2022)

Abstract Trastuzumab, an anti-HER2 monoclonal antibody developed by Roche, is now a standard of care for treating HER2 overexpressing cancers. However, patients treated with trastuzumab generally develop resistance to the drug within a year after initiation of the treatment. Pertuzumab, another anti-HER2 monoclonal antibody developed by Roche, targets the domain 2 of the HER2 excellular domain (ECD) instead of the domain 4 to which trastuzumab binds and demonstrates enhanced antitumor activities when combined with trastuzumab. Here, we developed a tetravalent bispecific antibody (BsAb) which targets the domain 2 and 4 of the HER2 ECD simultaneously. Using time-lapse microscopy, we showed that the BsAb induced aggregation of HER2 on NCI-N87 tumor cells, possibly indicating that the receptors could be crosslinked by the BsAb intermolecularly. Furthermore, the tetravalent BsAb induced aggregation faster than did the bivalent BsAb. Importantly, the tetravalent BsAbs exhibited superior tumor cell growth inhibition to that of the two parental monoclonal antibodies alone or combined. In line with the aggregation rates, the tetravalent BsAb was also more potent in inhibiting tumor cell growth than that of the bivalent BsAb. Thus we provide a piece of evidence that the BsAbs targeting two distinct domains of HER2 simultaneously might induce the receptor aggregation which might associate with the enhanced inhibition of tumor cell growth. Citation Format: Lan Deng, Jie Zhao, Xiaoqing Meng, Aotian Xiao, Zhenping Zhu, Haomin Huang. Aggregation of HER2 receptors on the tumor cell surface induced by a novel anti-HER2 bispecific antibody led to enhanced tumor cell growth inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5287.
Abstract 1034: Pharmacological GLUT3 salvage augments the efficacy of vitamin C induced TET2 restoration in AML cells
Authors: Jun Liu, Suji Min, Seojeong Kim, Daehyeon Gwak, Junshik Hong, Sungsoo Yoon
Journal: Cancer Research (2022)

Abstract Background and purpose: Vitamin C has been demonstrated to regulate hematopoietic stem cells (HSC) frequencies and leukemogenesis by augmenting and restoring TET2 function, potentially acting as a novel treatment strategy for leukemia. In a previous study (Liu et al, 2020 Br J Cancer), we showed that GLUT3, a major vitamin C transporter in acute myeloid leukemia (AML) cells, was significantly decreased in AML blasts compared with normal hematopoietic cells, which impedes TET2 restoration and promotes leukemia progression. Although GLUT3 could be a potential biomarker to predict the vitamin C treatment efficiency, a remaining question was whether GLUT3 can be a druggable target in AML. In this study, we aim to investigate the therapeutic value of GLUT3 salvage in AML Methods: GLUT3 salvage was conducted on GLUT3 deficient AML cell line OCI-AML3 using GLUT3 overexpression lentivirus transduction or AICAR (an AMPK activator, Phase 3) treatment. The 5hmC DNA dot blotting assay was carried out to explore the TET2 function. The leukemic phenotypes were evaluated using soft agar colony formation assay, migration assay, and invasion assay. Results: To verify if turning on GLUT3 enhances the efficacy of vitamin C treatment, the GLUT3 overexpression lentivirus or empty vector lentivirus was transduced into the OCI-AML3 cell line. The transcription level of SLC2A3 (gene encoded GLUT3) was increased to 8 times in the GLUT3 overexpression cell line. Then, 5hmC DNA dot blotting results showed that GLUT3 overexpression further significantly raised the 5hmC level after 250 µM vitamin C treatment. Consistent with augmentation of TET2 function, turning on GLUT3 with vitamin C treatment alleviated leukemic phenotypes compared with empty vector group. Pharmacological GLUT3 salvage using AICAR 0.5 mM 48 hours could achieve the same effect as lentivirus transduction, in terms of GLUT3 expression level, augmentation of TET2 function, and enhancement of vitamin C anti-leukemic effect. Notably, AICAR treatment only induced GLUT3 expression while showed no effect on GLUT5. Conclusion: GLUT3 salvage could augment the efficacy of vitamin C induced TET2 restoration in AML cells. Pharmacological GLUT3 salvage using AICAR sheds new light on overcoming GLUT3 deficiency in AML. Citation Format: Jun Liu, Suji Min, Seojeong Kim, Daehyeon Gwak, Junshik Hong, Sungsoo Yoon. Pharmacological GLUT3 salvage augments the efficacy of vitamin C induced TET2 restoration in AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1034.
Engineering Approaches for Breast Cancer Diagnosis: A Review
Authors: Arif Mohd. Kamal, Tushar Sakorikar, Uttam M. Pal, Hardik J. Pandya
Journal: IEEE Reviews in Biomedical Engineering (2022)

Breast cancer is a leading cause of mortality among women. The patient's survival rate is uncertain due to the limitations in the accuracy of diagnosis and effective monitoring during cancer treatment. The key to efficaciously controlling cancer on a larger scale is effective diagnosis at an early stage of cancer by distinguishing the vital signatures of the diseased from the normal breast tissue. The breast tissue is a heterogeneous turbid media that exhibits multifaceted bulk tissue properties. Various sensing modalities can yield distinct tissue behavior for cancer and adjacent normal tissues, serving as a basis for cancer diagnosis. A novel multimodal diagnostic tool that can concurrently assess the optical, electrical, and mechanical bulk tissue properties can substantially augment the clinical findings such as histopathology, potentially aiding the clinician to establish an accurate and rapid diagnosis of cancer. This review aims to discuss the clinical and engineering aspects along with the unmet challenges of these physical sensing modalities, primarily in the field of optical, electrical, and mechanical. The challenges of combining two or more of these sensing modalities that can significantly enhance the effectiveness of the clinical diagnostic tools are further investigated.
Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming
Authors: Faye A H Cooles, Jessica Tarn, Dennis W Lendrem, Najib Naamane, Chung MA Lin, Ben Millar, Nicola J Maney, Amy E Anderson, Nishanthi Thalayasingam, Julie Diboll, Vincent Bondet, Darragh Duffy, Michael R Barnes, Graham R Smith, Sandra Ng, David Watson, Rafael Henkin, Andrew P Cope, Louise N Reynard, Arthur G Pratt, John D Isaacs
Journal: Annals of the Rheumatic Diseases (2022)

An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.
Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8+ T Cells
Authors: Snehanshu Chowdhury, Anwesha Kar, Debaleena Bhowmik, Anupam Gautam, Debashree Basak, Ishita Sarkar, Puspendu Ghosh, Deborpita Sarkar, Alvina Deka, Paramita Chakraborty, Asima Mukhopadhyay, Shikhar Mehrotra, Soumen Basak, Sandip Paul, Shilpak Chatterjee
Journal: Cancer Research (2022)

Abstract Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose–citrate–acetyl CoA circuit in IL12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)–dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate–containing media in vitro acquired critical metabolic features of IL12-stimulated CD8+ T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T-cell therapy. Significance: IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8+ T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells.
Abstract 5258: Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics
Authors: Katherine R. Ramsey, Patricia H. Chapman, Guadalupe R. Palos, Maria A. Rodriguez
Journal: Cancer Research (2022)

Abstract Introduction: The number of deaths occurring among cancer survivors continues to be an outcome of concern. Our survivorship clinics provide risk stratification care for patients who have completed their curative treatment and are seen annually in a site-specific clinic. Here we describe mortality rates among adult patients receiving care in eleven site-specific survivorship clinics. Procedures: We conducted an analysis of 29,418 adult patients seen in our survivorship program from 2008-2021. Medical records were reviewed and categorized by each survivorship clinic. Eligibility criteria were: patients ≥18, treated for curative intent, completed their primary course of treatment, past the highest risk of recurrence, and transitioned based on site-specific survivorship algorithms. Descriptive statistics summarize the results. Results: There were 26475 survivors alive and 2943 deaths (Table 1). Of those alive, the greatest number were diagnosed with breast, genitourinary, and gastrointestinal malignancies. Death rates ranged from 2% to 38%, with the highest percent in stem cell transplant, head and neck, and gynecology malignancy survivors. 29% of deceased patients had died within one year of their transition from oncology care to survivorship clinics. Conclusions: Our results indicate differences in mortality risk among different cancer survivors; those who received transplants or were diagnosed with gynecologic or head/neck cancers had higher death rates. Survivors in these groups have short and long-term health risks which may require more proactive care. Current analyses are underway on the cause of death among patients who passed away within the first year of the transition to survivorship. Table 1. Total Number of Patients Seen by Clinic, Alive or Deceased Status, and Average Years Between First Appointment and Death (N=29418) Clinic Total No. No. Alive Percent Alive No. Deaths PercentDeaths Avg Years from First Appt to Death Breast 11972 11219 94% 753 6% 4 GI 837 787 94% 50 6% 3 GU 4264 3952 93% 312 7% 4 Gyn 1284 1175 91% 109 8% 4 Head &amp; Neck 2763 2482 90% 281 10% 3 Lymphoma 759 707 93% 52 7% 4 Melanoma 1234 1174 95% 60 5% 3 Sarcoma 87 85 98% 2 2% 1 Stem Cell Transplant 3141 1917 61% 1224 39% 1 Thoracic 489 461 94% 28 6% 2 Thyroid 2588 2516 97% 72 3% 4 Citation Format: Katherine R. Ramsey, Patricia H. Chapman, Guadalupe R. Palos, Maria A. Rodriguez. Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5258.
Abstract 5493: Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in solid tumors
Authors: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Haritha Polimati, Sridhar Veeraraghavan, Swaroop Vakkalanka
Journal: Cancer Research (2022)

Abstract Introduction: The Poly (ADP-ribose) polymerase (PARP) family plays an important role in the regulation of transcription, apoptosis and DNA damage response. Several PARP inhibitors have been approved for the treatment of BRCA-mutated ovarian, breast and pancreatic cancer. Through ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects either as monotherapy or in combination with established therapy across various solid tumor types. Herein, we describe the efficacy of RP12146 as a single agent and in combination with approved therapies in preclinical models of solid tumors. Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 as a single agent or in combination with approved agents in various solid tumor cell lines. Apoptosis was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. Anti-tumor potential of RP12146 as a single agent or in combination with chemotherapeutic agents was tested in OVCAR-3 and NCI-H69 Xenografts. Expression of downstream PAR, PARP-trapping, and cleaved PARP expression were determined in cell lines and xenograft tumor samples by Western blotting. Plasma and tumor concentration of RP12146 in NCI-H69 xenograft samples were also determined. Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Combination of RP12146 with Temozolomide, Topotecan, Lurbinectedin, and Abemaciclib demonstrated either additive or synergistic effects manifested by an inhibition in growth of solid tumor cell lines. RP12146 exhibited anti-tumor potential with TGI of 28% and 21.8% as a single agent in OVCAR-3 and NCI-H69 Xenograft model respectively. In NCI-H69 xenograft model, RP12146 in combination with cisplatin exhibited TGI of 69.3 %. Conclusion: Data demonstrate the therapeutic potential of RP12146 as single agent and in combination in solid tumors. RP12146 is currently being evaluated in Phase 1 clinical trials in patients with locally advanced or metastatic solid tumors (NCT05002868). Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Haritha Polimati, Sridhar Veeraraghavan, Swaroop Vakkalanka. Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5493.
Abstract 1868: Targeting adenosine deaminase enhances anticancer effects of 3'-deoxyadenosine in uveal melanoma
Authors: Su-Chan Lee, Lujain Alaali, HyukJean Kwon, Mohammed Rigi, Charles G. Eberhart
Journal: Cancer Research (2022)

Abstract Uveal melanoma, which arises from melanocytes located in the uveal tract, is one of the most common primary intraocular cancers. GNAQ and GNA11 mutations, which are detected most of primary uveal melanoma, activate MAPK signaling pathway, increasing cancer cell proliferation, tumor progression and growth. BAP1 mutation is highly associated with liver metastasis and death. However, there are no good therapeutic compounds for uveal melanoma treatment in clinic. 3’-deoxyadenosine (cordycepin) is an adenosine analog which inhibits growth of several types of cancer. However, its anticancer effects have been showed in limited cancer cell lines. In addition, action mechanism of 3’deoxyadenosin is poorly understood. In this study, we found different adenosine deaminase (ADA) expression or activity affects different anticancer results in uveal melanoma. Inhibition of ADA using either siRNA or pharmacologic approaches sensitized tumors to 3’-deoxyadenosine in vitro and in vivo, resulting in increased apoptosis, reduced clonogenic capacity and slower migration of uveal melanoma cells in vitro. These potent ADA-dependent anti-tumor effects were also seen in various cancer cell lines. Therefore, we suggest the potential of adenosine deaminase (ADA) as both a biomarker predicting response to 3’-deoxyadenosine, and a target for combination therapy. Citation Format: Su-Chan Lee, Lujain Alaali, HyukJean Kwon, Mohammed Rigi, Charles G. Eberhart. Targeting adenosine deaminase enhances anticancer effects of 3'-deoxyadenosine in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1868.
Abstract 1445: Influence of neighborhood deprivation on the DNA epigenome in cancerous breast tissue from African American and European American women
Authors: Brittany D. Lord, Emily Rossi, Tiffany Dorsey, Maeve Kiely, Ruby Hutchinson, Stefan Ambs
Journal: Cancer Research (2022)

Abstract Low socioeconomic status (SES) associates with early onset of chronic diseases and reduced life-expectancy. This relationship is only partly explained by unhealthy behavioral habits and inadequate access to health care. Chronic life stress is more prevalent in low SES communities and has been shown to affect DNA methylation and the immune system. Yet, the biological processes that mediate the impact of SES on health to promote the development of chronic diseases like cancer remain poorly understood. Our study aims to uncover whether DNA methylation is linked to neighborhood socioeconomic deprivation and to a biology that causes inflammation and changes to the immune environment, thereby promoting breast cancer progression and affecting response to therapy. These differences have been characterized in 181 breast tumors (108 African American (AA), 73 European American (EA)). We geocoded the addresses of our participants and linked these data to a Census-level neighborhood deprivation index (NDI). Statistically significant associations between NDI, race and methylation beta values were determined using linear regression followed by Benjamini-Hochbergcorrection. Of the 18 CpG sites that differed between individuals with low and high neighborhood deprivation, 3 were hypermethylated in women with high neighborhood deprivation. We also used methylCIBERSORT to estimate immune subpopulation differences by race group, breast cancer subtype, and ND. For AA women with aggressive triple negative breast cancer, neighborhood deprivation was significantly positively correlated with absolute immune cell scores (p=0.011), including a higher absolute score for endothelial cell expression (p=0.006) and eosinophils (p=0.049). Our findings give insight into how socioeconomic position and neighborhood deprivation may affect cancerous mammary gland biology by altering DNA methylation patterns. Citation Format: Brittany D. Lord, Emily Rossi, Tiffany Dorsey, Maeve Kiely, Ruby Hutchinson, Stefan Ambs. Influence of neighborhood deprivation on the DNA epigenome in cancerous breast tissue from African American and European American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1445.
Death of Pioneers in Research on Tropical Disease
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal